Redox-sensitive hyaluronic acid-cholesterol nanovehicles potentiate efficient transmembrane internalization and controlled release for penetrated "full-line" inhibition of pre-metastatic initiation.

Metastatic breast cancer is a major cause of cancer-related mortality worldwide. The tumor-specific penetration and triggered drug release for "full-line" inhibition of pre-metastatic initiation are of essential importance in improving mortality rates. Here, a crosslinked, redox-sensitive amphiphilic conjugate (cHLC) was constructed with a combination of features, including hyaluronic acid (HA)-mediated tumor active targeting, lipoic acid (LA) core-crosslinking based bio-stability and reducibility, and lipid raft anchoring-promoted HA-mediated endocytosis through cholesterol (CHO) modification for the penetrated co-delivery of paclitaxel (PTX) and the multi-targeted anti-metastatic agent, silibinin (SB). Resultantly, the nanodrug (cHLC/(PTX + SB)) demonstrated enhanced tumor cytoplasm-selective rapid drug delivery in a 4T1 model both in vitro and in vivo. The released SB efficiently sensitized cells to PTX treatment and inhibited the whole process of pre-metastatic initiation including epithelial-to-mesenchymal transition (EMT), local and blood vessel invasion. The exquisite design of this delivery system provides a deep insight into enhancing focus accessibility of multi-targeted drugs for an efficient inhibition of tumor metastasis.

Potential role of the compound Eucommia bone tonic granules in patients with osteoarthritis and osteonecrosis: A retrospective study.

BACKGROUND: Osteoarthritis is a major source of pain, disability, and socioeconomic cost worldwide. Osteonecrosis is a disabling disorder that frequently occurs in the younger population aged from 20-50 years. The compound Eucommia bone tonic granules, a traditional Chinese medicine, can alleviate the damage of osteoarthritis and osteonecrosis. AIM: To investigate the potential role of the compound Eucommia bone tonic granules (Eucommia) in the treatment of patients with osteoarthritis and osteonecrosis. METHODS: One-hundred forty osteoarthritis and osteonecrosis cases admitted to our hospital from January 2013 to December 2017 were selected. Patients were divided into two groups: Eucommia-meloxicam group and meloxicam group. Clinical efficacy and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) score were evaluated according to the evaluation criteria of orthopedic diseases. The levels of bone-GLA protein, interleukin-17, recombinant human S100 calcium binding protein A12, sphingosine 1-phosphate, cystatin C, creatinine, and hemoglobin in peripheral blood were determined. RESULTS: The total effective rate in the two osteoarthritis groups was not different, but the total effective rate in the two osteonecrosis groups was significantly different. The overall efficacy of Eucommia-meloxicam group was superior to that of the meloxicam group. WOMAC showed that pain, stiffness, and dysfunction in the two groups of osteoarthritis and osteonecrosis before and after treatment were significantly different. The concentration of recombinant human S100 calcium binding protein A12, sphingosine 1-phosphate, cystatin C, creatinine, and hemoglobin before and after treatment in the Eucommia-meloxicam group and meloxicam group of osteoarthritis and osteonecrosis were significantly different, and the two treatment groups were significantly different from each other for osteoarthritis. CONCLUSION: Our findings indicate that Eucommia can effectively enhance the curative effect of meloxicam, and the combination of Eucommia and meloxicam is superior to meloxicam alone.

Carbon Disulfide Induces Embryo Implantation Disorder by Disturbing the Polarization of Macrophages in Mice Uteri.

Carbon disulfide (CS2) induces embryo implantation disorders. Macrophages participate in the process of pregnancy. Therefore, we want to explore the effects of CS2 exposure on polarization and immune function of macrophages in pregnant mice uteri. The exposure times were gestation days 3 (GD3), 4 (GD4), and 5 (GD5), and the observation end points were arranged in a time series after CS2 exposure. The uterine tissues were collected to detect the expression levels of macrophages cytokines (IL-6, IL-12, TGF-ß1, and Vegf-a) and downstream regulatory cytokines of Th1-type (IL-2 and IFN-γ) and Th2-type (IL-10 and IL-4) by flow cytometry, ELISA, and q-PCR. The results showed that, compared with the controls, the ratios of M1/M2 macrophages in the endometrium significantly increased by 96%, 110%, and 177% at the GD4, GD6, and GD7 observation end points after GD3 exposure and increased about 3.88-fold and 2.37-fold at the GD6 and GD7 observation end points after GD4 exposure, respectively. In contrast, the ratio of M1 and M2 macrophages significantly reduced by 53% at the GD5 observation end point after GD3 exposure. Meanwhile, the expression levels of IL-6 were significantly increased about 2.00-fold for mRNA and 1.60-fold for protein at GD4 observation end points after GD3 exposure, and the mRNA levels of IL-12 increased about 3.61-fold at the GD6 observation end points after GD4 exposure. The mRNA levels of TGF-ß1 were significantly decreased by 41%, 25%, and 20% at the GD7 observation end points after exposure at GD3, GD4, and GD5, and the expression levels of Vegf-a mRNA and protein were decreased. Furthermore, the ratio of IL-2/IL4, IL-2/IL-10, IFN-γ/IL-4, and IFN-γ/IL-10 in the uterine tissue was significantly increased at the exposure groups. These findings suggest that the imbalanced polarization of macrophages is the key regulator in the progress of CS2-induced embryo loss.

Preparation of a poly(ethyleneimine) embedded phenyl stationary phase for mixed-mode liquid chromatography.

A poly(ethyleneimine) embedded phenyl mixed-mode stationary phase was prepared through epoxide ring opening reaction. Elemental analysis (EA), Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA) were used to characterize whether functional groups have been modified on the surface of silica successfully. The researches of chromatographic performance for designed column were divided to four parts. The retention behavior under reversed-phase mode was studied using polycyclic aromatic hydrocarbons (PAHs), positional isomers and alkylbenzenes. The retention characteristic under hydrophilic interaction mode was studied by nucleosides, nucleobases and flavonoids. The chromatographic performance of anion exchange mode was evaluated by benzoic acids and phenols. Due to a high content of amino and phenyl groups on the stationary phase, aromatic amines were chosen for the evaluation of retention mechanisms of benzene ring attraction and amino repulsion. The investigations about effects of mobile phase constitution and pH on retention demonstrated the mixed-mode retention mechanisms of the column. Furthermore, due to amino selectivity of the column, a method for the rapid separation and determination of phenylenediamines in hair dye was established. And both linear correlation coefficients of p-diaminobenzene and m-diaminobenzene in concentration range from 0.1 to 30 µg mL-1 were over 0.999. In conclude, the prepared mixed-mode stationary phase could realize various separation modes by adjusting chromatographic conditions, and it had the potential for the rapid separation and determination of aniline compounds in various complex samples.

Down-regulation of uterine LIF expression induced by the hormonal level disorder causes embryo implantation loss after mice exposed to carbon disulfide at peri-implantation.

Carbon disulfide (CS2) exposure can cause embryo implantation loss but the mechanism remains unclear. Earlier study revealed that the 4th day of gestation (GD4) and GD5 were the most sensitive exposure time on which the number of implanted embryos decreased obviously in mice. Leukemia inhibitory factor (LIF) in maternal uterine tissue is involved in embryo implantation, which is produced by endometrium and Th2 cells that participate in cellular adhesion of maternal-fetal interface. We herein investigated the effect of CS2 on the expression of LIF in uterine tissue and its regulatory mechanism in Kunming mice. Exposure was on GD3, GD4, GD5 and GD6, respectively, single administration (631.4 mg/kg), and the indexes were arranged in time series after exposure. The results showed that LIF gene breakage was captured at the 18th hour after exposure by Comet-FISH and the protein and mRNA of LIF in uterine tissue were down-regulated after exposure through the peri-implantation period. In addition, sex steroid hormones, progesterone (P4) and oestrogen (E2) were detected since they can stimulate synthesis of LIF from endometrial cells. Results showed that P4 and E2 in serum were down-regulated at all the endpoints of CS2 exposure groups. These findings suggested that the down-regulated LIF induced by the decreased P4 and E2 after mice exposure to CS2 might be important reasons for implantation disorders.

[DNA damage of splenic lymphocytes in pregnant mice exposed to carbon disulfide in implantation phase].

OBJECTIVE: To investigate the DNA damage of splenic lymphocytes in pregnant mice exposed to carbon disulfide (CS2) in the implantation phase and to explore the mechanism of abnormal implantation induced by CS2 from the perspective of immune injury. METHODS: Mice were exposed to CS2 at different doses or at different time points in the implantation phase to establish model 1 and model 2. For model 1, mice were assigned to four groups to receive a single intraperitoneal injection of low-dose CS2 (0.1 LD50, 157.8 mg/kg), middle-dose CS2 (0.2 LD50, 315.7 mg/kg), and high-dose CS2 (0.4 LD50, 631.4 mg/kg) as well as an equal volume of olive oil (control) on gestational day (GD) 4. For model 2, mice were assigned to four groups to receive a single intraperitoneal injection of CS2 (0.4 LD50, 631.4 mg/kg) or an equal volume of olive oil (control) on GD3, GD4, GD5, and GD6. At the end, single cell suspension of splenic lymphocytes was prepared. Cell viability was measured by trypan blue staining, and the DNA damage of splenic lymphocytes was evaluated by alkaline single cell gel electrophoresis assay. RESULTS: The middle-dose and high-dose exposure groups showed significantly more DNA damage of splenic lymphocytes than the control group (P < 0.01); there was significant regression relationship between indicators of DNA damage and exposure doses (P < 0.01). The GD3, GD4, GD5, and GD 6 exposure groups showed significantly more DNA damage of splenic lymphocytes than the control group (P < 0.01), and the GD 4 exposure group had the most DNA damage. CONCLUSION: Exposure to CS2 in the implantation phase can induce DNA damage of splenic lymphocytes in pregnant mice, and the DNA damage was aggravated with the increase in CS2 concentration. GD4 may be the sensitive time point for DNA damage of splenic lymphocytes induced by CS2 in pregnant mice.